The overall objective of this proposal is to provide information of critical importance for the logical use of combination chemotherapy in the treatment of neoplastic diseases. Initially, we will elucidate the cytotoxic effects exerted by specific agents that modify deoxyribonucleotide metabolism in human myelocytic leukemia cells (B type). The second objective is to study the interaction of deoxyribonucleoside analogs with other types of drugs. Due to the importance of ribonucleotide reductase (RR) in deoxyribonucleotide metabolism, and the inadequate characterization of this enzyme in human tissues, we propose to purify and characterize this enzyme. An understanding of the kinetic allosteric nature, and general properties of this enzyme, will facilitate a study not only of the regulatory controls of the enzyme in the intact cell, but also of the regulation of turnover of the enzyme. Attempts will be made by manipulation of RR activity to influence deoxyribonucleotide metabolism. Many other factors could also alter deoxyribonucleotide metabolism which may or may not be related to RR. Experiments are proposed to study the various factors, e.g., hormones that affect deoxyribonucleotide metabolism and their relationship to the sensitivity of the cell toward various deoxyribonucleoside analogs. The information will be of value in understanding how to use deoxyribonucleoside analogs in cancer chemotherapy most effectively.